TY - JOUR
T1 - Modeling, synthesis, and biological evaluation of potential retinoid X receptor (RXR) selective agonists
T2 - Novel analogues of 4-[1-(3,5,5,8,8- Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and (E)-3-(3-(1,2,3,4-tetrahydro-1,1,4,4,6-pentamethylnaphthalen-7-yl) -4-hydroxyphenyl)acrylic acid (CD3254)
AU - Jurutka, Peter
AU - Kaneko, Ichiro
AU - Yang, Joanna
AU - Bhogal, Jaskaran S.
AU - Swierski, Johnathon C.
AU - Tabacaru, Christa R.
AU - Montano, Luis A.
AU - Huynh, Chanh C.
AU - Jama, Rabia A.
AU - Mahelona, Ryan D.
AU - Sarnowski, Joseph T.
AU - Marcus, Lisa M.
AU - Quezada, Alexis
AU - Lemming, Brittney
AU - Tedesco, Maria A.
AU - Fischer, Audra J.
AU - Mohamed, Said A.
AU - Ziller, Joseph W.
AU - Ma, Ning
AU - Gray, Geoffrey M.
AU - Van Der Vaart, Arjan
AU - Marshall, Pamela
AU - Wagner, Carl
N1 - Copyright:
Copyright 2013 Elsevier B.V., All rights reserved.
PY - 2013/11/14
Y1 - 2013/11/14
N2 - Three unreported analogues of 4-[1-(3,5,5,8,8-pentamethyl-5-6-7-8- tetrahydro-2-naphthyl)ethynyl]benzoic acid (1), otherwise known as bexarotene, as well as four novel analogues of (E)-3-(3-(1,2,3,4-tetrahydro-1,1,4,4,6- pentamethylnaphthalen-7-yl)-4-hydroxyphenyl)acrylic acid (CD3254), are described and evaluated for their retinoid X receptor (RXR) selective agonism. Compound 1 has FDA approval as a treatment for cutaneous T-cell lymphoma (CTCL), although treatment with 1 can elicit side-effects by disrupting other RXR-heterodimer receptor pathways. Of the seven modeled novel compounds, all analogues stimulate RXR-regulated transcription in mammalian 2 hybrid and RXRE-mediated assays, possess comparable or elevated biological activity based on EC50 profiles, and retain similar or improved apoptotic activity in CTCL assays compared to 1. All novel compounds demonstrate selectivity for RXR and minimal crossover onto the retinoic acid receptor (RAR) compared to all-trans-retinoic acid, with select analogues also reducing inhibition of other RXR-dependent pathways (e.g., VDR-RXR). Our results demonstrate that further improvements in biological potency and selectivity of bexarotene can be achieved through rational drug design.
AB - Three unreported analogues of 4-[1-(3,5,5,8,8-pentamethyl-5-6-7-8- tetrahydro-2-naphthyl)ethynyl]benzoic acid (1), otherwise known as bexarotene, as well as four novel analogues of (E)-3-(3-(1,2,3,4-tetrahydro-1,1,4,4,6- pentamethylnaphthalen-7-yl)-4-hydroxyphenyl)acrylic acid (CD3254), are described and evaluated for their retinoid X receptor (RXR) selective agonism. Compound 1 has FDA approval as a treatment for cutaneous T-cell lymphoma (CTCL), although treatment with 1 can elicit side-effects by disrupting other RXR-heterodimer receptor pathways. Of the seven modeled novel compounds, all analogues stimulate RXR-regulated transcription in mammalian 2 hybrid and RXRE-mediated assays, possess comparable or elevated biological activity based on EC50 profiles, and retain similar or improved apoptotic activity in CTCL assays compared to 1. All novel compounds demonstrate selectivity for RXR and minimal crossover onto the retinoic acid receptor (RAR) compared to all-trans-retinoic acid, with select analogues also reducing inhibition of other RXR-dependent pathways (e.g., VDR-RXR). Our results demonstrate that further improvements in biological potency and selectivity of bexarotene can be achieved through rational drug design.
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U2 - 10.1021/jm4008517
DO - 10.1021/jm4008517
M3 - Article
C2 - 24180745
AN - SCOPUS:84887928768
VL - 56
SP - 8432
EP - 8454
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 21
ER -